Plasma Complement Levels Are Associated with Primary Graft Dysfunction and Mortality after Lung Transplantation

Shah, Rupal J.; Emtiazjoo, A.; Diamond, Joshua M.; Smith, Patricia; Roe, David; Wille, Keith; Orens, Jonathan B.; Ware, Lorraine B.; Weinacker, Ann; Lama, Vibha N.; Bhorade, Sangeeta; Palmer, Scott M.; Crespo, Maria; Lederer, David J.; Cantu, Edward; Eckert, George J.; Christie, Jason D.; Wilkes, David S.

doi:10.1164/rccm.201312-2121le

Cited by 28 publications

(30 citation statements)

References 12 publications

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“…This difference is consistent with the hypothesis that PGD is linked to tissue viability or immune activation that may restrict TTV levels in the lung. PGD is associated with activation of multiple innate immune responses (15–17) which might control TTV but also mediate injury contributing to PGD. Alternatively, in addition to immune cells, TTV has also been reported to replicate in respiratory epithelia and lung tissue (65, 66).…”

Section: Discussionmentioning

confidence: 99%

“…Host genetic variation in genes involved in oxidant stress responses and innate immunity correlate with risk of PGD (13, 14). PGD has also been associated with inflammasome activation, pattern recognition receptor signaling, and complement activation within the allograft (15–17). These studies raise the possibility of a microbial contribution to pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

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The Perioperative Lung Transplant Virome: Torque Teno Viruses Are Elevated in Donor Lungs and Show Divergent Dynamics in Primary Graft Dysfunction

Abbas

Diamond

Chehoud

et al. 2017

American Journal of Transplantation

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Primary graft dysfunction (PGD) is a principal cause of early morbidity and mortality after lung transplantation, but its pathogenic mechanisms are not fully clarified. Thus far, studies using standard clinical assays have not linked microbial factors to PGD. We previously used comprehensive metagenomic methods to characterize viruses in lung allografts >1 month post-transplant and found that levels of Anellovirus, mainly Torque teno viruses (TTV), were significantly higher than in non-transplant healthy controls. Here we used quantitative PCR to analyze TTV and shotgun metagenomics to characterize full viral communities in acellular bronchoalveolar lavage from donor organs and post-reperfusion allografts in PGD and non-PGD lung transplant recipient pairs. Unexpectedly, TTV DNA levels were 100-fold elevated in donor lungs compared with healthy adults (p=0.0026). Although absolute TTV levels did not differ by PGD status, PGD cases showed a smaller increase in TTV levels from pre- to post-transplant than did control recipients (p=0.041). Metagenomic sequencing revealed mainly TTV and bacteriophages of respiratory tract bacteria, but no viral taxa distinguished PGD cases from controls. These findings suggest that conditions associated with brain death promote TTV replication, and that greater immune activation or tissue injury associated with PGD may restrict TTV abundance in the lung.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Perioperative Lung Transplant Virome: Torque Teno Viruses Are Elevated in Donor Lungs and Show Divergent Dynamics in Primary Graft Dysfunction

Abbas

Diamond

Chehoud

et al. 2017

American Journal of Transplantation

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“…Circulating levels of the anti-coagulant protein C are lower in those with PGD compared to those without PGD while levels of the pro-inflammatory protein plasminogen activator inhibitor-1 (PAI-1) are higher in those with PGD 21 . Changes in plasma levels of complement protein 5a (C5a), a potent neutrophil and lymphocyte chemoattractant, are associated with PGD after transplant 22 . Plasma levels of these proteins are also excellent predictors of obesity, with PAI-1 being one of the top 5 circulating biochemical predictors of total, abdominal, visceral and liver fat 23 .…”

Section: Discussionmentioning

confidence: 99%

Adipose Gene Expression Profile Changes With Lung Allograft Reperfusion

Diamond

Arcasoy

McDonnough

et al. 2017

American Journal of Transplantation

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Obesity is a risk factor for primary graft dysfunction, a form of lung injury resulting from ischemia reperfusion after lung transplantation, but the impact of ischemia reperfusion on adipose tissue is unknown. We evaluated differential gene expression in thoracic visceral adipose tissue (VAT) before and after lung reperfusion. Total RNA was isolated from thoracic VAT sampled from 6 subjects enrolled in the Lung Transplant Body Composition study before and after allograft reperfusion and quantified using the Human Gene 2.0 ST array. KEGG pathway analysis revealed enrichment for genes involved in complement and coagulation cascades and Jak-STAT signaling pathways. Overall, 72 genes were upregulated and 56 genes were down-regulated in the post-reperfusion time compared with baseline. Long pentraxin-3 (PTX3), a gene and plasma protein previously associated with PGD, was the most upregulated gene (19.5 fold increase, p=0.04). Fibronectin leucine rich transmembrane protein (FLRT3), a gene associated with cell adhesion and receptor signaling, was the most down-regulated gene (4.3 fold decrease, p=0.04). Ischemia reperfusion has a demonstrable impact on gene expression in visceral adipose tissue in our pilot study of non-obese, non-PGD lung transplant recipients. Future evaluation will focus on differential adipose tissue gene expression and the development of PGD after transplant.

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“…A variety of clinical risk factors for PGD have been identified with contributions from the donor (3)(4)(5)(6)(7), the recipient (3)(4)(5)(7)(8)(9)(10), and operative variables (4,5,8,11). In addition, a number of biomarkers have been associated with increased risk of PGD, including markers of innate and adaptive immune activation, epithelial and endothelial injury, coagulation, vascular permeability, and lipid peroxidation (2,(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Despite identification of these clinical and biomarker predictors of PGD, the mechanisms leading to PGD are not well understood, and there are no specific therapeutic interventions for PGD.…”

Section: Introductionmentioning

confidence: 99%

Cell-free hemoglobin promotes primary graft dysfunction through oxidative lung endothelial injury

et al. 2018

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Plasma Complement Levels Are Associated with Primary Graft Dysfunction and Mortality after Lung Transplantation

Cited by 28 publications

References 12 publications

The Perioperative Lung Transplant Virome: Torque Teno Viruses Are Elevated in Donor Lungs and Show Divergent Dynamics in Primary Graft Dysfunction

The Perioperative Lung Transplant Virome: Torque Teno Viruses Are Elevated in Donor Lungs and Show Divergent Dynamics in Primary Graft Dysfunction

Adipose Gene Expression Profile Changes With Lung Allograft Reperfusion

Cell-free hemoglobin promotes primary graft dysfunction through oxidative lung endothelial injury

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